SPPL2B

protein-coding

signal peptide peptidase like 2B, the group of Peptidase family A22

Gene summary

This gene encodes a member of the GXGD family of aspartic proteases. The GXGD proteases are transmembrane proteins with two conserved catalytic motifs localized within the membrane-spanning regions. This enzyme localizes to endosomes, lysosomes, and the plasma membrane. It cleaves the transmembrane domain of tumor necrosis factor alpha to release the intracellular domain, which triggers cytokine expression in the innate and adaptive immunity pathways. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_152988.3

Inheritance

—

ClinVar variants

U:14B:2

Top phenotype

—

Max pathogenic AF

—

Genomic locus

chr19:2,328,615-2,355,095

External References & Databases

Ensembl (ENSG00000005206)

Transcript & Mutation Effects

hg38 • Region Span ~26.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SPPL2B variants in ClinVar

1 Conditions Cataloged

not specifiedTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_152988.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar			3
missense			7 clinvar	2 clinvar		9
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	0	14	2	0	16

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 58 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_152988.3	RefSeq	NP_694533.1	15	MANE Select
ENST00000613503.5	Ensembl	ENSP00000478298.1	15	MANE Select
NM_001077238.2	RefSeq	NP_001070706.1	14	Standard
ENST00000586332.5	Ensembl	ENSP00000480311.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

membrane protein ectodomain proteolysis
regulation of tumor necrosis factor-mediated signaling pathway
membrane protein intracellular domain proteolysis
membrane protein proteolysis
regulation of immune response

Molecular Function

protein binding
aspartic endopeptidase activity, intramembrane cleaving
protein homodimerization activity

Cellular Component

Golgi membrane
nucleoplasm
lysosomal membrane
centrosome
plasma membrane

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Intramembrane-cleaving aspartic protease (I-CLiP) that cleaves type II membrane signal peptides in the hydrophobic plane of the membrane. Functions in ITM2B and TNF processing (PubMed:16829952, PubMed:16829951, PubMed:17965014, PubMed:19114711, PubMed:22194595). Catalyzes the intramembrane cleavage of the anchored fragment of shed TNF-alpha (TNF), which promotes the release of the intracellular domain (ICD) for signaling to the nucleus (PubMed:16829952, PubMed:16829951). May play a role in the regulation of innate and adaptive immunity (PubMed:16829952). Catalyzes the intramembrane cleavage of the simian foamy virus processed leader peptide gp18 of the envelope glycoprotein gp130 dependently of prior ectodomain shedding by furin or furin-like proprotein convertase (PC)-mediated cleavage proteolysis (PubMed:23132852). {ECO:0000269|PubMed:16829951, ECO:0000269|PubMed:16829952, ECO:0000269|PubMed:17965014, ECO:0000269|PubMed:19114711, ECO:0000269|PubMed:22194595, ECO:0000269|PubMed:23132852}.;

Recessive Scores

pRec: 0.122

Intolerance Scores

RVIS EVS: -0.14
RVIS percentile EVS: 43.77

Essentials

Indispensability pred.: N
Indispensability score: 0.341